Microemulsion &amp; sub-micron emulsion process &amp; compositions

ABSTRACT

An oil in water microemulsion or sub-micron emulsion composition for dermal delivery of at least one pharmaceutically active ingredient, is provided. The composition includes an oil phase dispersed throughout a water phase, the oil phase including at least one member selected from the group consisting of an animal oil, a mineral oil, a vegetable oil, a silane member, a siloxane, an ester, a fatty acid, a fat, a halogen compound, and an alkoxylated alcohol; and at least one lipophilic surfactant, the water phase including at least one hydrophilic surfactant, water and optionally a non-surfactant amphiphilic compound, the weight ratio of the at least one hydrophilic surfactant to the at least one lipophilic surfactant being approximately 9.0:1.0 to 2.0:3.0.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/216,668, filed Aug. 31, 2005, which claims priority to U.S.Provisional Patent Application Ser. No. 60/606,278, filed Aug. 31, 2004and U.S. Provisional Patent Application Ser. No. 60/670,722, filed Apr.12, 2005, the contents of which are both hereby expressly incorporatedby reference in their entirety.

FIELD OF THE INVENTION

This invention relates to a method of formulation of microemulsions andsub-micron emulsions useful in cosmetic and therapeutic applications inthe field of dermatology. In particular, the invention relates tomethods of formulation of stable microemulsions and sub-micron emulsionswhich may contain ingredients which are known to be disruptive of thephysical state of the formulation. The invention also relates tocosmetic and therapeutic microemulsion and sub-micron emulsioncompositions arising from these methods. Methods of cosmetic andtherapeutic treatment using the microemulsions and sub-micron emulsionsare encompassed by this invention as are the uses of the compositionsarising from the formulation method in appropriate treatments.

BACKGROUND

The size of a particle is critical to its ability to cross the skinbarrier and therefore its ability to deliver a pharmaceutically activeingredient for the treatment of local or systemic medical conditions ofthe patient concerned. As particles become smaller (particularly below100 nm), the percentage of exposed surface area of a particle inproportion to its total volume when compared to unrefined material isincreased, and hence its potential efficacy is increased.

The characteristics of sub-micron particles in their application to thedelivery of pharmaceutically active ingredients across the skin barriermay be summarised as follows:

Particle size Description Characteristics 300-1000 nm EmulsionBlue-white, milky liquid, reasonable physical stability. Particlesreside on skin surface → transdermal delivery. 100-300 nm Sub-micronBluish, translucent liquid. Enhanced Emulsion physical stability.Particles reside on skin surface → enhanced transdermal delivery. 10-100nm Microemulsion Translucent-transparent liquid. Excellent physicalstability. Particles reside on skin surface → enhanced transdermaldelivery. <5 nm Nanoparticles/ Translucent-transparent liquid. Nano-Excellent physical stability. Particles dispersion/ reside on skinsurface, within stratum Micelles corneum and in hair follicles → optimaltransdermal delivery.

Because of the desirable characteristics of so called microemulsions,and sub-micron emulsions, attempts have been made to perfect the meansof their manufacture. Essentially, the much higher ratio of emulsifierto disperse phase is that feature which differentiates a microemulsionfrom a macroemulsion. The aim is to stabilise oil phases in waterphases, or vice versa. The nature of the emulsifier (or surfactant) usedis clearly very important. Oil in water micro emulsions are particularlydifficult to formulate and, generally speaking, simply adapting themode, or means of homogenization, or increasing the amount of emulsifierpresent will not guarantee the product is a microemulsion. The choice ofemulsifier is reportedly critical to the success of the formulation (BK:MicroEmulsions Theory and Practice, Prince, Leon (ed) pp 33-50, AcademicPress, NY, USA, 1977).

Water in oil systems are made by blending the oil and emulsifier, with alittle heat if necessary, and then adding water. The amount of waterthat can be added to a given system of emulsifier and oil may not alwaysbe high enough for the application in mind. In that event, it becomesnecessary to try other emulsifiers. When one is found that permits thedesired water uptake, it may be convenient from a processing viewpointto add the mixture of emulsifier and oil to the water. Again, warmingthe system may hasten the mixing process. In systems of oil, water andemulsifier that are capable of forming microemulsions, the order ofmixing does not affect the end result.

The simplest way to make an oil in water microemulsion is to blend theoil and emulsifier and then pour this liquid mixture into the water withmild stirring. Another technique is to make a crude macroemulsion of theoil and one of the emulsifiers, for example, a soap. By using lowvolumes of water a gel is formed. This gel is then changed into a clearsolution by titration with a second surface active agent like analcohol. This system may then be transformed into an opalescent oil inwater microemulsion of the desired concentration by further addition ofwater. By far the most common method of making an oil in watermicroemulsion, especially in the trial and error stage, however, is bythe so-called inversion process.

In actual practice, oils which are capable of being microemulsified,i.e. “emulsifiable oils”, as opposed to those which may be dispersed inmicellar solution, invert by the slow addition of water from a fluidwater in oil dispersion through a viscoelastic gel stage to a fluid oilin water microemulsion. 100% emulsifier on the weight of the oil may beemployed. After careful blending, with heat if necessary, water is addedto the blend in a beaker. This is done in successive, small aliquots. Ifthe chemistry is right, a clear, transparent water in oil dispersionfirst forms. This is fluid. As more water is added, at about equalvolumes of water and oil/emulsifier blend, the system begins to becomemore viscous. As more water is added, it becomes very viscous,ultimately becoming a heavy gel. At this point it is frequently helpfulto apply heat to thin the gel and facilitate passage through this stage.With the addition of more water, the gel eventually thins out to a fluidoil in water microemulsion which can readily be identified by itsclarity or opalescence.

The highly viscous intermediate gel stages are not microemulsions butare sometimes so called, as in the case of ringing gels used as hairpomades. These systems are actually liquid crystalline phases and occurbecause of the particular sequence of mixing employed in forming themicroemulsion.

Given the importance of the emulsifier to the successful formulation ofthe microemulsion, systems have been developed to assist in selection ofthe emulsifier. One such system (Shiroda, K., J. Colloid Interface Sci,24, 4 (1967)) is that based upon the temperature at which an emulsifiercauses an oil in water emulsion to invert to a water in oil emulsion. Itis known as the Phase Inversion Temperature (PIT) System. It providesinformation about various oils, phase volume relationships, and theconcentration of emulsifier required. The system is established on theproposition that the hydrophilic lipophilic balance (the “HLB”) of anon-ionic surfactant changes with temperature and that the inversion ofemulsion type occurs when the hydrophilic and lipophilic tendencies ofthe emulsifier just balance each other. No emulsion forms at thistemperature. Emulsions stabilised with non-ionic agents are oil in watertypes at low temperature and invert to water in oil types at elevatedtemperature. It goes without saying that use of more than one emulsifierin a composition may positively influence the formulation of amicroemulsion. PIT techniques require a significant input of energy inorder to attain a sub-micron emulsion. The process requires hightemperature so as to render the ethoxylated surfactant hydrophobic,whereby the oil in water emulsion becomes a water in oil emulsion, andthereafter, the conversion of the water in oil dispersion to a oil inwater dispersion is effected upon subsequent cooling of the formulation.At least because of the degradative effect that heat has upon certainactive ingredients, it would be desirable to reduce the energyrequirements for such processes as this is likely to reduce the risk ofcrystallisation of poorly soluble active ingredients occurring uponnormal temperature cycling of the stored product

Microemulsion technology has been the subject of relatively intenseinvestigation since the late 1950's when hair gels using the technologywere first developed.

One patent U.S. Pat. No. 6,333,362 (L'OREAL) describes an ultrafinefoaming oil in water emulsion where the particle size of the oilparticles constituting the oil phase range from 50-1000 nm. The PITtechnique is used to manufacture the formulation. Example 1 describes aprior art formulation as follows:

Phase 1 % dicapryl ether 7.7 Isocetyl stearate 3.0 cetearyl isononanoate4.0 beheneth-9 4.5

Phase 2 % Distilled water 14.7 Preservative q.s

Phase 3 % distilled water q.s.100 sodium lauryl ether sulphate 5.0where the sodium lauryl ether sulphate in phase 3 acts as the foamingagent on dispensing the product from its pressurised can. To prepare theformulation phases 1 and 2 were heated separately to 60° C. andhomogenised. Phase 2 was poured slowly, with stirring, onto Phase 1 andthe mixture was heated as far as the phase inversion temperature, whichwas around 85° C. The heating was stopped and Phase 3 was poured inunheated and the mixture was allowed to cool while slow stirring wasmaintained.

Nanoemulsions which contain an amphiphilic lipid phase composed ofphospholipids, water and oil are known in the art. These emulsionsexhibit the disadvantage of being unstable on storage at conventionalstorage temperatures, namely between 0 and 45° C. They lead to yellowcompositions and produce rancid smells which develop several days afterstorage. One example of such an emulsion is described in WO 03/08222(BEIERDORF AG)

In practice there are challenges in formulating microemulsions. Thepoint at which the composition inverts from an oil in water or water inoil formulation, respectively, to a water in oil or oil in waterformulation, known as the “set point” needs to be carefully monitored.If the set point is not reached before the product is poured out,inversion will not occur, and so a microemulsion will not be achieved.High set points in particular can be difficult to achieve and maintain.Additives can be used to lower the set point but these can also have theeffect of destabilising the microemulsion resulting in undesirablealteration of the viscosity of the microemulsion, cloudiness, and canalso cause loss of invertible character altogether. Furthermore,although high levels of emulsifier can be desirable, on the other hand,high emulsifier content can lead to skin and eye irritation of the user.

Petrolatum, which is desirably used in dermatological compositions forits occlusive and emollient properties, is considered too difficult toincorporate in microemulsion formulations because of its viscosity.

Another ingredient which is desirable in dermatological applications ispropylene glycol for its capacity as a penetration enhancer. However, ithas been reported as undesirable in microemulsion technology because ofits potential to disrupt or destabilise the formulation. WO 94/08603(SMITHKLINE BEECHAM CORPORATION) teaches the avoidance of propyleneglycol and other polyhydroxyl alcohol cosurfactants because of theprocessing and stability issues they introduce.

Another challenge in the application of microemulsions to the field ofdermatology is the solubilisation of the pharmaceutically activeingredients in the formulations. Some pharmaceutically activeingredients are highly water soluble, or in the alternative are highlyoil soluble. Others are sparingly soluble. A pharmaceutically activeingredient in solution provides better penetration than one insuspension and, both of these provide better penetration than a drug asa solid. In the case where a pharmaceutically active ingredient is noteasily solubilised, the need for an additive such as propylene glycolwhich can assist in penetration, is obvious, but conversely the ease offormation of a microemulsion is diminished.

In light of the foregoing, it is an object of this invention to identifymethods of formulating microemulsions and sub-micron emulsionformulations which may act as a vehicle for the delivery of apharmaceutically active ingredient across the skin barrier for cosmeticor therapeutic purposes. It is a secondary object to achieve a means ofincorporating one or more microemulsion disrupting substances, such aspetrolatum and/or propylene glycol into such a microemulsion orsub-micron emulsion at the same time maintaining the viscosity,appearance, stability and efficacy of the formulation.

Any discussion of documents, devices, acts or knowledge in thisspecification is included to explain the context of the invention. Itshould not be taken as admission that any of the information formed partof the prior art base or the common general knowledge in the relevantart on or before the priority date of the present subject matter.

SUMMARY OF INVENTION

The present invention provides a process for the preparation of an oilin water (O/W) microemulsion or sub-micron emulsion composition fordermal delivery of at least one pharmaceutically active ingredient, themethod including the steps of

a) admixing a first part including at least one selected from the groupconsisting of animal, mineral or vegetable oils, silanes, siloxanes,esters, fatty acids, fats, halogen compounds and alkoxylated alcohols;and one or more lipophilic surfactants, and a second part includingwater and at least one hydrophilic surfactant to achieve homogeneity,

b) heating the mix of step a) to a phase assembly temperature in therange of 40-99° C., preferably 45-95° C., more preferably 65-85° C. withcontinuous mixing to obtain an oil in water microemulsion or sub-micronemulsion,

c) allowing said microemulsion or sub-micron emulsion to cool, and

d) adding a third part to said microemulsion or sub-micron emulsion at atemperature between 2° C. and said phase assembly temperature, saidthird part if necessary being premixed and heated until the componentsare dissolved and including at least one component selected from thegroup consisting of non-surfactant amphiphilic type compound, surfactantand water.

This method, in one preferred embodiment of the present invention, canbe achieved in such a way that the first and the second part arerespectively preheated to a temperature of 40-99° C., preferably 45-95°C., and more preferably 65-85° C. and then admixed to homogeneity; andsubsequently the second part is added to the first part at a temperatureof 40-99° C., preferably 45-95° C., and more preferably 65-85° C. withcontinuous mixing whereby a microemulsion or sub-micron emulsion isformed at a phase assembly temperature.

The phase assembly temperature can be determined visually by theachievement of translucence in the composition or by measures such asconductivity which peaks and then is maintained at a plateau whilstphase assembly occurs.

It has been found that where a non-surfactant amphiphilic type compoundsuch as the polyol is added, if such a compound added together with thesecond part as would conventionally be the case, a microemulsion orsub-micron emulsion is not formed. However, by adding the so calledthird part, phase assembly occurs at a lower temperature than would beexpected and moreover, this phase appears to assist in maintaining themicroemulsion or sub-micron emulsion characteristics of the formulationduring storage at normal temperatures. This is a particularly usefulphenomenon where it is desirable to use pharmaceutically activeingredients which tend towards insolubility except in solvents includinga polyol and/or alcohol. By effectively lowering the temperature atwhich phase assembly is achieved, active ingredients which are degradedby exposure to temperature are more preserved than is the case in priorart formulations. It is thus believed that the shelf life of theformulations according to the present invention can be prolonged ascompared to prior art compositions.

The water phase of the microemulsion or sub-micron emulsion is desirablyadded in two aliquots, 2/3 and 1/3; in aliquots more preferably of about70-80% and 20-30% by weight of the total water phase. More preferablystill, the second aliquot is added after the microemulsion or sub-micronemulsion has formed, at a temperature substantially below thetemperature of the first aliquot, and at a rapid rate so as to reducethe overall temperature of the composition preferably to below about 60°C. whereby the microemulsion or sub-micron emulsion structure is fixed.

A pharmaceutically active ingredient may suitably be incorporated in anyone or more of the three parts of the formulation during preparation.The most appropriate part of incorporation will depend on the solubilitycharacteristics of the pharmaceutically active ingredient and thepreferred release profile of the resulting formulation. Preferably, apharmaceutically active ingredient may be added in the third part withor without the non-surfactant amphiphilic type compound.

An occlusive agent which has the effect of adding emollient quality tothe formulation is also desirably incorporated in the microemulsions orsub-micron emulsions by inclusion in the preparation of the first partof the composition. Preferably the occlusive agent is petrolatum.

The microemulsion or sub-micron emulsion resulting from the process isdesirably gassed using a suitable propellant so as to be deliverable asa foam or mousse.

The present invention also provides an oil in water microemulsion orsub-micron emulsion composition for dermal delivery of at least onepharmaceutically active ingredient including an oil phase dispersedthroughout a water phase, said oil phase including at least one selectedfrom the group consisting of animal, mineral or vegetable oils, silanes,siloxanes, esters, fatty acids, fats, halogen compounds and alkoxylatedalcohols; and at least one lipophilic surfactant, and said water phaseincluding at least one hydrophilic surfactant, water and optionallynon-surfactant amphiphilic compound, the weight ratio of said at leastone hydrophilic surfactant to said at least one lipophilic surfactantbeing approximately 9.0:1.0 to 2.0:3.0.

Preferably, the present composition includes surfactants having anaggregated HLB number between 8.0 and 15.0, more preferably between 10and 12 and still more preferably between 9.7 and 11.8. More preferably,the lipophilic surfactant has an HLB number of less than 10, and thehydrophilic surfactant has an HLB number of greater than 10.

The pharmaceutically active ingredient may suitably be in either or bothsaid oil and/or water phases. The most appropriate phase ofincorporation will depend on the solubility characteristics of thepharmaceutically active ingredient and the preferred release profile ofthe formulation.

An occlusive agent which has the effect of adding emollient quality tothe formulation is also desirably present in the oil phase of themicroemulsions or sub-micron emulsions. Preferably the occlusive agentis petrolatum.

The present invention also provides a method of medical or cosmetictreatment of a dermal condition including applying to the skin of apatient requiring such treatment an effective amount of oil in watermicroemulsion or sub-micron emulsion composition including at least onepharmaceutically active ingredient, including an oil phase dispersedthroughout a water phase, said oil phase including at least one selectedfrom the group consisting of animal, mineral or vegetable oils, silanes,siloxanes, esters, fatty acids, fats, halogen compounds and alkoxylatedalcohols; and at least one lipophilic surfactant, and said water phaseincludes at least one hydrophilic surfactant, water and optionally anon-surfactant amphiphilic type compound, the weight ratio of the atleast one hydrophilic surfactant to the at least one lipophilicsurfactant being approximately 9.0:1.0 to 2.0:3.0.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic flow diagram showing one preferred embodiment ofthe invention in which an ethanol-free 0.05% clobetasol propionatemicroemulsion is prepared. The method is described in detail in Example6.

FIG. 2 is a graphical representation of one preferred method ofpreparation of formulations according to the invention utilising thecorticosteroid clobetasol propionate.

FIG. 3 is a timeline of one preferred method of preparation offormulations according to the invention utilising the corticosteroiddesonide.

FIG. 4 is a graphical representation of the method depicted in thetimeline of FIG. 3.

FIG. 5 shows the effect on particle size distribution of varying theratio of surfactants in betamethasone valerate compositions according tothe invention.

FIG. 6 shows the conductivity response from heating various compositionsaccording to the invention to the assembly temperature, and then coolingthem.

FIG. 7 is a schematic flow diagram of the process used to produce theformulation subject of the clinical trials described in Example 14.

FIG. 8 is a schematic flow diagram showing one preferred embodiment ofthe invention in which 0.2% and 10% lactic acid sub-micron emulsion isprepared.

FIG. 9 is a schematic flow diagram showing one preferred embodiment ofthe invention in which 1% pramoxine sub-micron emulsion foam isprepared.

FIG. 10 is a table showing the foam quality of a formulation accordingto one preferred embodiment of the invention in which unpreserved 1%pramoxine semi-micron foam is evaluated at two typical extremetemperature of 10° and 30° C.

FIG. 11 is a table showing the foam quality of a formulation accordingto one preferred embodiment of the invention in which preserved 1%pramoxine semi-micron foam is evaluated at two typical extremetemperature of 10° and 30° C.

DETAILED DESCRIPTION OF THE INVENTION

Without being bound by theory, it is thought that when thenon-surfactant, amphiphilic components such as propylene glycol, atypical polyol used in dermatological formulations because of itscapacity as a penetration enhancer, and a solvent is present in thewater phase, it interferes with the assembly or packing formation of thesurfactants present in the composition around the oil particles andprevents the formation of microemulsion sized particles. The same isalso true of a preservative, such as phenoxy ethanol or benzyl alcohol.By the process of the invention, it is possible to reproduciblymanufacture microemulsion or sub-micron emulsion particles at lowtemperature in the range 100-600 nm with the majority of particles beingin the 100-200 nm range. The exclusion of propylene glycol from theinitial water/oil phase mixing appears to allow the surfactants presentthe ability to pack into a microemulsion structure at a lowertemperature than would otherwise be achieved and with the assistance oftemperature manipulation, to fix in place.

Throughout this specification, the term “non-surfactant, amphiphilictype compound” should be understood to include compounds which aremiscible with water and other organic excipients, and which may act as asolvent for a pharmaceutically active ingredient not soluble in water,but may also have other functions in the formulations. Examples ofcompounds falling into the scope of this term are alcohols includingpropylene glycol, benzyl alcohol, dichlorobenzyl alcohol,phenoxyethanol, transcutol P, panthenol; polyols such as glycerin;alkoxylated alcohols including polyethylene glycol of varying molecularweight; heterocyclic compounds including methylpyrrolidine; and aproticsolvents including dimethyl sulfoxide. Preferred non-surfactant,amphiphilic type compounds are phenoxyethanol and propylene glycol.Phenoxyethanol may be present in amounts of up to 2% w/w and propyleneglycol is desirably present in amounts of up to 50% w/w, more preferablyin amounts of up to 30% w/w, and still more preferably in amounts of upto 25% w/w.

Throughout this specification the term “water soluble” when used inrelation to a pharmaceutically active ingredient should be taken to meancompounds which have significant aqueous solubility and which typicallyexhibit low solubility in non-aqueous solvents.

The term “water insoluble” when used in relation to pharmaceuticallyactive ingredients should be understood to include compounds which haveno appreciable aqueous solubility and which typically favour hydrophobicsolvents.

The term “phase assembly temperature” when used throughout thisspecification should be taken to mean the temperature at which maximumtranslucency of the dispersion is observed when preparing the oil inwater microemulsions or sub-micron emulsions according to the processesdescribed. This temperature point is consistent with the temperature atwhich tiny particles are assembled.

Preferably, in the present methods, processes and compositions accordingto the invention, the oil phase includes an occlusive agent which hasthe effect of adding an emollient quality to the formulations. Onepreferred occlusive agent is petrolatum. Although present at roomtemperature as a solid, using the process of preparation of theinvention, it has been found that petrolatum can be successfullyincorporated into a formulation which is of low viscosity and suitablefor pressurised delivery. Other occlusive agents which may beincorporated in the compositions and according to the processes of theinvention are microcrystalline wax, bees wax, paraffin wax and lanolinwax. Notably petrolatum, a preferred occlusive agent, is made up ofapproximately 50% w/w mineral oil and approximately 50% w/wmicrocrystalline and paraffin wax. Desirably the waxy component shouldnot account for more than 25% w/w of the total oil phase.

Preferably in the present methods, processes and compositions of theinvention the water phase of the formulation is added in two aliquots;in aliquots more preferably of about 70-80% and 20-30% by weight of thetotal water phase. More preferably still, the second aliquot is addedafter the microemulsion or sub-micron emulsion has formed, at atemperature substantially below the temperature of the first aliquot,and at a rapid rate so as to reduce the overall temperature of thecomposition preferably to below about 60° C. whereby the microemulsionor sub-micron emulsion structure is fixed. The two aliquots may both bean homogenous mix of all components in the phase or may be differentcomponents of the phase e.g. water together with non surfactantamphiphilic type compound and/or surfactant alone.

A pharmaceutically active ingredient may be introduced in any one ormore of the three parts of preparation with the result that in themicroemulsion or sub-micron emulsion according to the invention, theactive ingredient may be present in the continuous water phase or thediscontinuous oil phase or both. By appropriate manipulation, theformulations of the invention may be designed as slow or delayed releasecompositions by, for example, the location of the active ingredient inthe phase in which it is substantially or completely insoluble.

Where the pharmaceutically active ingredient is introduced in the firstpart, optionally solvents, co-solvents and coupling agents may also bepresent. Preferred solvents may include acetyl tributylcitrate, tributylcitrate and other appropriate solvents. Coupling agents help link orimprove miscibility of oils that are immiscible with the oil phase andassist in achieving clarity. Suitable coupling agents according to theinvention are organic, non-ionic, virtually insoluble in water, misciblewith oily/fatty/lipophilic materials and exhibit solubility for pastyand/or solid fatty/lipophilic materials. Isopropyl myristate is onesuitable coupling agent. Others include, but are not limited to,polyglyceryl esters, isocetyl alcohol, octyl methoxycinnamate, octyldimethyl PABA, tocopheryl acetate and lanolin alcohols.

Preferably the pharmaceutically active ingredient is introduced in thesecond part, and more preferably it is introduced in the third partwhere it appears that its presence alongside the non-surfactant,amphiphilic type compound serves to improve the transdermal performanceof the composition. A non surfactant amphiphilic type compound alsoappears to assist in distributing the pharmaceutically active ingredientthroughout the desired phase. In particular, where the pharmaceuticallyactive ingredient is desirably present in both the oil phase and thewater phase, non water miscible organic solvent is required in the oilphase and a water miscible organic solvent is required in the waterphase. As the amount of water miscible organic solvent is increased, therate of diffusion of the active agent across the skin barrier is seen toincrease. A slower flux is observed when the active is dissolved withinthe oil phase that contains organic solvent. Particularly in the casethat the pharmaceutically active ingredient is only sparingly soluble inwater or insoluble in water, the addition of an increased amount oforganic solvent to the water phase can assist in partitioning thepharmaceutically active ingredient into the water phase. Thus where theactive agent is present in the continuous water phase, the active agentis available for rapid treatment of the patient's condition. Activeagent in the oil phase may be available through other skin diffusionpathways for longer term treatment regimes.

The water phase may also include buffers such as, but not limited to,citric acid and potassium citrate, disodium EDTA and tetrasodium EDTA,disodium EDTA and disodium phosphate, and preservatives such as, but notlimited to phenoxyethanol, benzyl alcohol, dichlorobenzyl alcohol,sorbic acid and potassium sorbate.

Where the pharmaceutically active ingredient is included in the waterphase, this phase may also include a functional water soluble organiccomponent including humectants, solvents for the active ingredient andpenetration enhancers. Substances which may be included in theformulations of the invention in the water phase and which fall into oneor more of these categories include but are not limited to propylenecarbonate, transcutol, ethoxydiglycol, polyhydric alcohols such asglycerol, sorbitol and propylene glycol.

The pharmaceutically active ingredient may be any chemical substance orcombination of chemical substances which have registration for thepurposes of cosmetic or medical treatment and which are dermallydeliverable. The pharmaceutically active ingredients can be present inthe composition in different forms, depending on which form yields theoptimum delivery characteristics. Thus, in the case of drugs, it can bein its free base or acid form, or in the form of salts, esters, or anyother pharmacologically acceptable derivatives, or as components ofmolecular complexes, analogues, metabolites or pro-drugs.

In one preferred embodiment of the invention, the pharmaceuticallyactive ingredient can be a compound which is insoluble or sparinglysoluble in the water. In another preferred embodiment of the invention,the pharmaceutically active ingredient can be a water soluble compound.

Preferably the active ingredient is a corticosteroid selected from thegroup consisting of betamethasone valerate, desonide and clobetasolpropionate or vitamin D or vitamin A analogues. The pharmaceuticallyactive ingredient may alternatively be a drug that is normally deliveredby oral, parenteral, percutaneous, perungual or rectal route.

Other examples of pharmaceutically active ingredients that can beadministered by the compositions of this invention include, but are notlimited to:

Cardioactive medications, for example, organic nitrates such asnitroglycerine, isosorbide dinitrate, and isosorbide mononitrates;quinidine sulfate; procainamide; thiazides such as bendroflumethiazide,chlorothiazide, and hydrochlorothyazide; nifedipine; nicardipine;adrenergic blocking agents, such as timolol and propranolol; verapamil;diltiazem; captopril; clonidine and prazosin.

Androgenic steroids, such as testosterone, methyltestosterone andfluoxymesterone.

Estrogens, such as conjugated estrogens, esterified estrogens,estropipate, 17beta estradiol, 17beta-estradiol valerate, equilin,mestranol, estrone, estriol, 17beta-ethinyl estradiol, anddiethylstilboestrol. Progestational agents, such as progesterone,19-norprogesterone, norethindrone, norethindrone acetate, melengestrol,chlormadinone, ethisterone, medroxyprogesterone acetate,hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel,17alpha hydroxyprogesterone, dydrogesterone, dimethisterone,ethinylestrenol, norgestrel, demegestone, promegestone, and megestrolacetate.

Drugs having an action on the central nervous system, for examplesedatives, hypnotics, antianxiety agents, analgesics and anaesthetics,such as chloral, buprenorphine, naloxone, haloperidol, fluphenazine,pentobarbital, phenobarbital, secobarbital, codeine, lidocaine,tetracaine, dyclonine, dibucaine, methocaine, cocaine, procaine,mepivacaine, bupivacaine, etidocaine, prilocaine, benzocaine, fentanyl,and nicotine.

Nutritional agents, such as vitamins, essential amino adds and essentialfats.

Anti-inflammatory agents, such as hydrocortisone, cortisone,dexamethasone, fluocinolone, triamcinolone, medrysone, prednisolone,flurandrenolide, prednisone, halcinonide, methylprednisolone,flurandrenolide, prednisone, halcinonide, methylprednisolone,fludrocortisone, corticosterone, paramethasone, betamethasone,ibuprofen, naproxen, fenoprofen, fenbufen, flurbiprofen, indoprofen,ketoprofen, suprofen, indomethacin, piroxicam, aspirin, salicylic acid,diflunisal, methyl salicylate, phenylbutazone, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, and the like.

Respiratory agents, such as theophylline and beta2-adrenergic agonistssuch as albuterol, terbutaline, metaproterenol, ritodrine, carbuterol,fenoterol, quinterenol, rimiterol, solmefamol, soterenol, andtetroquinol.

Sympathomimetics, such as dopamine, norepinephrine, phenylpropanolamine,phenylephrine, pseudoephedrine, amphetamine, propylhexedrine andepinephrine. Miotics, such as pilocarpine, and the like. 12 Cholinergicagonists, such as choline, acetylcholine, methacholine, carbachol,bethanechol, pilocarpine, muscarine, and arecoline.

Antimuscarinic or muscarinic cholinergic blocking agents such asatropine, scopolamine, homatropine, methscopolamine, homatropinemethylbromide, methantheline, cyclopentolate, tropicamide,propantheline, anisotropine, dicyclomine, and eucatropine. Mydriatics,such as atropine, cyclopentolate, homatropine, scopolamine, tropicamide,eucatropine and hydroxyamphetamine.

Psychic energizers such as 3-(2-aminopropyl)indole,3-(2-aminobutyl)indole, and the like.

Anti-infectives, such as antivirals, eg acyclovir, allylamines and inparticular terbinafine hydrochloride and naftifine hydrochlorideantibiotics, including penicillin, tetracycline, chloramphenicol,sulfacetamide, sulfamethazine, sulfadiazine, sulfamerazine,sulfamethizole and sulfisoxazole; antivirals, including idoxuridine;antibacterials, such as erythromycin and clarithromycin; and otheranti-infectives including nitrofurazone and the like.

Vitamins such as vitamins A, D and E, and derivatives thereof, such asretinal, tretinoin, isotretinoin, retinol, retinoxytrimethylsilane,retinyl acetate, retinyl linoleate, retinyl palmitate, retinylpropionate and other vitamin A analogues for vitamin A derivatives,alfacalcidol, calcitriol, tacalcitol, calcipotriol, calcifediol,colecalciferol, dihydrotachysterol, ergocalciferol, doxercalciferol,falecalcitriol, maxacalcitol, paracalcitol and other vitamin D analoguesfor vitamin D derivatives, and tocopherols, tocophersolan, tocopherylacetate, tocopheryl glucoside, tocopheryl linoleate, tocopherylnicotinate, tocopheryl oleate, tocopheryl succinate and other vitamin Eanalogues for vitamin E derivatives.

Hydroxyacids useful for various conditions and disorders including agespots, keratoses, skin wrinkles etc., such as 2-Hydroxyacetic acid;2-hydroxypropanoic acid (=lactic acid); 2-methyl 2-hydroxypropanoicacid; 2-hydroxybutanoic acid; phenyl 2-hydroxyacetic acid; phenyl2-methyl 2-hydroxyacetic acid; 3-phenyl 2-hydroxyacetic acid;2,3-dihyroxypropanoic acid; 2,3,4-trihydroxybutanoic acid;2,3,4,5,6-pentahydroxyhexanoic acid; 2-hydroxydodecanoic acid;2,3,4,5-tetrahydroxypentanoic acid; 2,3,4,5,6,7-hexahydroxyheptanoicacid; diphenyl 2-hydroxyacetic acid; 4-hydroxymandelic acid;4-chloromandelic acid; 3-hydroxybutanoic acid; 4-hydroxybutanoic acid;2-hydroxyhexanoic acid; 5-hydroxydodecanoic acid; 12-hydroxydodecanoicacid; 10-hydroxydecanoic acid; 16-hydroxyhexadecanoic acid;2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid;3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3-methoxymandelic acid;2-hydroxy-2-methylbutanoic acid; 3-(2-hydroxphenyl) lactic acid;3-(4-hydroxyphenyl) lactic acid; hexahydromandelic acid;3-hydroxy-3-methylpentanoic acid; 4-hydroxydecanoic acid;5-hydroxydecanoic acid; aleuritic acid. 2-Hydroxypropanedioic acid;2-hydroxybutanedioic acid; erythraric acid; threaric acid; arabiraricacid; ribaric acid; xylaric acid; lyxaric acid; glucaric acid;galactaric acid; mannaric acid; gularic acid; allaric acid; altraricacid; idaric acid; talaric acid; 2-hydroxy-2-methylbutanedioic acid; orits salts;

Citric acid, isocitric acid, agaricic acid, quinic acid, glucuronicacid, glucuronolactone, galacturonic acid, galacturonolactone, uronicacids, uronolactones, ascorbic acid, dihydroascorbic acid,dihydroxytartaric acid, tropic acid, ribonolactone, gluconolactone,galactonolactone, gulonolactone, mannonolactone, citramalic acid, or itssalts; and

Pyruvic acid, hydroxypyruvic acid, hydroxypyruvic acid phosphate, theiresters; methyl pyruvate, ethyl pyruvate, propyl pyruvate, isopropylpyruvate; phenyl pyruvic acid, its esters; methyl phenyl pyruvate, ethylphenyl pyruvate, propyl phenyl pyruvate; formyl formic acid; its esters;methyl formyl formate, ethyl formyl formate, propyl formyl formate;benzoyl formic acid, its esters; methyl benzoyl formate, ethyl benzoylformate and propyl benzoyl formate; 4-hydroxybenzoyl formic acid, itsesters; 4-hydroxyphenyl pyruvic acid, its esters; 2-hydroxyphenylpyruvic acid and its esters. Lactic acid, salts thereof and mixturesthereof are preferred.

Anti-itch compounds such as local anesthetics, antihistamines,corticosteroids and anti-pruritics.

Local anesthetics including but not limited to articaine, bupivacaine,cinchocaine, ethyl parapiperidinoacetylaminobenzoate, etidocaine,levobupivacaine, lidocaine, mepivacaine, oxetacaine, prilocaine,ropivacaine, tolycaine, trimecaine, amylocaine, cocaine, propanocaine,proxymetacaine, benzocaine, butacaine, butoxycaine, butyl aminobenzoate,chloroprocaine, oxybuprocaine, parethoxycaine, procaine, propoxycaine,tetracaine, tricaine, diperodon, dyclonine, ethyl chloride, ketocaine,myrtecaine, octacaine, pramocaine (=pramoxine), propipocaine,quinisocaine, and the like, including salts thereof and mixturesthereof, with pramoxine and pramoxine HCl being preferred.

Antihistamines including but not limited to diphenhydramine,dimenhydrinate, perphenazine, triprolidine, pyrilamine, chlorcyclizine,promethazine, carbinoxamine, tripelennamine, brompheniramine,hydroxyzine, cyclizine, meclizine, clorprenaline, terfenadine, andchlorpheniramine.

Antipruritics including but not limited to calamine, camphor, methol,Palmitamide MEA, stearamide MEA, lactamide MEA, oleamide MEA, acetamideMEA, and mixtures thereof, some of these also having anti-inflammatoryeffects.

Humoral agents, such as the prostaglandins, natural and synthetic, forexample PGE1, PGF2alpha, and PGF2alpha, and the PGE1 analog misoprostol.

Antispasmodics, such as atropine, methantheline, papaverine,cinnamedrine, and methscopolamine.

Antidepressant drugs, such as isocarboxazid, phenelzine,tranylcypromine, imipramine, amitriptyline, trimipramine, doxepin,desipramine, nortriptyline, protriptyline, amoxapine, maprotiline, andtrazodone.

Anti-diabetics, such as insulin, and anticancer drugs such as tamoxifenand methotrexate.

Anorectic drugs, such as dextroamphetamine, methamphetamine,phenylpropanolamine, fenfluramine, diethylpropion, mazindol, andphentermine. Anti-allergenics, such as antazoline, methapyrilene,chlorpheniramine, pyrilamine and pheniramine.

Tranquilizers, such as reserpine, chlorpromazine, and antianxietybenzodiazepines such as alprazolam, chlordiazepoxide, clorazeptate,halazepam, oxazepam, prazepam, clonazepam, flurazepam, triazolam,lorazepam and diazepam.

Antipsychotics, such as thiopropazate, chlorpromazine, triflupromazine,mesoridazine, piperacetazine, thioridazine, acetophenazine,fluphenazine, perphenazine, trifluoperazine, chlorprathixene,thiothixene, haloperidol, bromperidol, loxapine, and molindone.

Decongestants, such as phenylephrine, ephedrine, naphazoline,Antipyretics, such as aspirin, salicylamide, and the like.

Antimigraine agents, such as dihydroergotamine and pizotyline.

Drugs for treating nausea and vomiting, such as chlorpromazine,perphenazine, prochlorperazine, promethazine, scopolamine, hyacinehydrobromide, triethylperazine, triflupromazine, and trimeprazine.

Anti-malarials, such as the 4-aminoquinolines, alpha-aminoquinolines,chloroquine, and pyrimethamine.

Anti-ulcerative agents, such as misoprostol, omeprazole, and enprostil.

Peptides and proteins, such as drugs for Parkinson's disease,spasticity, and acute muscle spasms, such as levodopa, carbidopa,amantadine, apomorphine, bromocriptine, selegiline (deprenyl),trihexyphenidyl hydrochloride, benztropine mesylate, procyclidinehydrochloride, baclofen, diazepam, dantrolene, insulin, erythropoietinand growth hormone.

Anti-estrogen or hormone agents, such as tamoxifen or human chorionicgonadotropin.

Nucleotides and nucleic acids (e.g. DNA).

The third part may be present in the compositions according to theinvention in an amount from 0.1% w/w to 50% w/w.

The first part of the methods, processes and compositions according tothe invention preferably makes up 1-30% w/w of the total resultingcomposition. Individual components of this phase preferably each have asolubility parameter of approximately 5.7-8.1 cal/cc and together, morepreferably, when combined, have a calculated solubility parameter ofapproximately 7.0-7.4 cal/cc and should still more preferably be in aliquid state at the phase assembly temperature of the composition.

Oils that may be used in the methods, processes and compositionsaccording to the invention may include but are not limited to one ormore of mineral oils, petrolatum, caprylic/capric triglyceride, peanutoil, cyclomethicone, cod liver oil, isopropyl myristate and alkoxylatedoils including ethoxylated, propoxylated or ethoxylated-propoxylatedoils. Cosmetic grade oils such as dioctyl cyclohexane, cetearylisonanoate, C12-C15 alkyl benzoate, oleyl oleate, octylhydroxy stearateand octyl dodecanol may also be suitable. In preferred processes,methods and compositions according to the invention, the oil phaseincludes petrolatum, mineral oil, esters and cyclomethicone. Still morepreferably, the oil phase includes petrolatum, mineral oil, an esterbeing isopropyl myristate, acetyl tributylcitrate, or tributylcitrateand cyclomethicone in an approximate ratio of 1:1:1:1. Still morepreferably the oil phase includes approximately 25% petrolatum, 25%mineral oil, 25% isopropyl myristate and 25% cyclomethicone. One of theproblems confronted with conventional emulsion formulations is theextent to which they have to be redispersed if, on standing, aseparation occurs. The ability to redisperse is important to thecommercial acceptability of a product. In the methods, processes andcompositions according to the invention, this issue has been addressedby optimising the oil phase to reduce the proportion of petrolatum,introduce co solvents and coupling agents and reduce the presence of anysolid surfactants that exhibit solubility in the oil phase whilstensuring the surfactant remains functional.

Other components of the oil phase might include but are not limited tolauryl lactate, isosteareth-2-octanoate, alk-oxylated derivates oflauric, oleic or stearic acid, each of which may act as emulsifiers,humectants, or coupling agents; octyl salicylate and oleyl oleate whichmay act as skin penetrants; polyglyceryl-3-laurate, diisopropyl sebacatewhich may act as an emollient, solubiliser or coupling agent or HydramolPGPL (PEG.PPG-8/3 laurate).

The total amount of oil in the oil phase may be in the amount of about1-30% w/w.

The nature of surfactants (also known as emulsifiers) which can beutilised in the compositions resulting from the preferred processes ofthe invention will vary, and as discussed in the preamble of thisspecification may be subject to some experimentation before beingperfected. Variations may arise as a result of the components of the oilphase selected, the pharmaceutically active ingredient and possibly eventhe temperature parameters under which the process is conducted.

Generally, commercial microemulsion gels are based on phosphate estersand non-ionic emulsifiers, although it is possible to formulate systemsbased on non-ionic emulsifiers alone. Ethoxylated fatty alcohols are themost popular non-ionic emulsifiers used. These include ethoxylates of:lanolin alcohols (laneths) oleyl alcohol (oleths), lauryl alcohol(laureths), cetyl alcohols (ceteths), stearyl alcohol (steareths),cetostearyl alcohols (ceteareths) and isocetyl alcohol (isoceteths).Phosphate esters include those based on ethoxylated lauryl alcohol(laureth phosphates) and ethoxylated oleyl alcohol (oleth phosphates).In general, the more ethoxylated a surfactant is, the higher its HLB,the higher the temperature at which a microemulsion or sub-micronemulsion is formed, and the larger the particle size of the resultingformulation. Ethoxylation has a greater effect on the ability of thecomposition to assemble as a microemulsion or sub-micron emulsion thandoes the carbon chain length of the surfactant.

When discussing emulsifiers for microemulsion gels, it is helpful tokeep in mind that a large molecular weight emulsifier and a smallmolecular weight oil may be the optimum combination.

In the processes, methods and compositions according to one preferredembodiment of the invention, lipophilic nonionic surfactants may beselected from the group consisting of fatty alcohols such as cetylalcohol, isocetyl alcohol or stearyl alcohol; glyceryl esters andderivatives thereof such as glyceryl monostearate and glycerylmonooleate; esters such as methyl glucose sesquistearate; sorbitanderivatives such as sorbitan laurate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan monooleate and sorbitan sesquioleate. Lipophilicanionic surfactants may be selected from the group consisting of fattyacids such as palmitic acid and stearic acid. Hydrophilic non-ionicsurfactants may be selected from the group consisting of alkoxylatedcarboxylic acids such as PEG 40 stearate; alkoxylated alcohols such asceteareth-12, -20 and -30, oleth 10 and laureth-4 and -23 andsteareth-4; sorbitan derivatives such as polysorbate 40, polysorbate 60and polysorbate 80; glyceryl esters and derivatives thereof such asPEG-40 hydrogenated castor oil and PEG-35 castor oil.

The minimum concentration of surfactant in the methods, processes andcompositions according to one form of the invention appears to be about1.8% w/w using 1% w/w oil phase. The maximum concentration of surfactantin the compositions according to one form of the invention appears to beabout 20.1% w/w using 10% w/w oil phase.

It also appears that the ratio of surfactant:oil may also contribute tothe ability of the compositions prepared according to the processes ofthe invention to form sub-micron emulsions and microemulsions. Apreferred ratio of surfactant:oil is approximately 1:3 to 3:1

In the compositions of the invention, the surfactant system includes atleast two surfactants, one lipophilic and one hydrophilic. Preferably,the surfactant system includes surfactants having an aggregated HLBnumber between 8.0 and 15.0, more preferably between 10 and 12 and stillmore preferably between 9.7 and 11.8. More preferably, the lipophilicsurfactants have an HLB number of less than 10, and the hydrophilicsurfactants have an HLB number of greater than 10. Preferred candidatesas surfactants in the compositions according to the invention aresorbitan laurate and cetyl alcohol used in the first oil phase, andCeteareth-20 or oleth 10 in the second water phase.

In a two surfactant system (one lipophilic and one hydrophilic), thepreferred range of concentration of hydrophilic:lipophilic surfactant isabout 9:1 to 1.0:1.0.

In a three surfactant system using one hydrophilic surfactant and twolipophilic surfactants, one preferred ratio of surfactants is 8:1:1 to4:5:1. That is the total hydrophilic:lipophilic ratio is preferably 4:1to 2:3.

In a four surfactant system using two hydrophilic surfactants and twolipophilic surfactants, one preferred ratio of surfactants is2.5:2.5:4.0:1.0 to 3.0:3.0:3.0:1.0. That is the totalhydrophilic:lipophilic ratio is preferably 3.0:2.0 to 1:1.

Other additives which may be present in the compositions preparedaccording to the invention not already mentioned include but are notlimited to preservatives such as phenoxyethanol, benzyl alcohol,dichlorobenzyl alcohol, sorbic acid and potassium sorbate; antioxidantssuch as BHT, humectants such as lactic acid, glycerine, urea and AjidewN-50/Sodium PCA; and polymers, thickeners or gums such as EudragitNE40D. These additives are typically organic and exhibit somemiscibility with water and other organic ingredients and may generallybe incorporated together with the active agent.

The compositions according to the invention may be in any physical formso as to suit their purpose. In a final fourth part, or a final fifthpart when a fourth part comprising a preservative is present, of theprocess of preparation of the microemulsions or sub-micron emulsions ofthe invention it is possible to introduce a propellant into themicroemulsion so that the composition may be dispensed as an aerosolfoam or mousse. In this case the propellant may be selected fromhydrocarbons such as P70; ethers such as dimethylether and halogencompounds such as Hydrofluorocarbon 134A. The propellant may be presentin amounts of about 5-20% w/w.

The microemulsion or sub-micron emulsion may also be formulated as agel, cream, lotion or patch depending on its purpose. For example,thickening agents such as sodium carboxymethyl cellulose or gellingagents such as the water soluble polymers, carbomer and xanthan may beadded when a gel formulation is required.

The following examples provide more details of the microemulsion orsub-micron emulsion formulations of the invention, preparation methodsand storage stability thereof; however, the following examples areprovided only to illustrate the scope of the invention but should not beconsidered to limit the scope to the examples as the skilled person willappreciate the means by which the following formulations may be alteredwhilst still resulting in formulations falling within the broadest scopeof the invention.

EXAMPLES

Examples 1 and 1A show a composition having surfactant ratios accordingto the prior art, and wherein propylene glycol, generally considereddisruptive of sub-micron emulsions is added together with otherconstituents in a single stage aqueous phase of the process. Theseexamples are provided for comparison purposes and do not illustrate theinvention.

Examples 2-5A show six different compositions using the pharmaceuticallyactive ingredients clobetasol propionate, desonide orbetamethasone-17-valerate in formulations according to preferredembodiments of the invention wherein the surfactant ratios are of thedesired ratio range. Examples 4 and 5 in accordance with the inventionare compositions which include propellant. The examples 2-5A may befurther processed into formulations useful as a lotion, spray, gel,paste, foam or any other suitable dosage form.

Example 1 Prior Art

20% PG/pH6 % w/w Phase 1 - Oil Phase Clobetasol Propionate 0.0475Petrolatum 7.50 Mineral Oil 5.00 Isopropyl Myristate 7.50 Cyclomethicone5.00 Cetyl Alcohol 2.00 Sorbitan Laurate 1.50 Phase 2 - Aqueous PhaseWater 38.7525 Ceteareth-20 6.50 Citric Acid 0.04 Potassium Citrate 0.16Propylene Glycol 20.00 Phenoxy Ethanol 1.00 Phase 3 - Propellant PhaseHydrocarbon Propellant P70 5.00 Total 100.00

Example 1A Prior Art

20% PG/pH 6 % w/w Phase 1 - Oil Phase Clobetasol Propionate 0.05Petrolatum 7.90 Mineral Oil 5.26 Isopropyl Myristate 7.90 Cyclomethicone5.26 Cetyl Alcohol 2.11 Sorbitan Laurate 1.58 Phase 2 - Aqueous PhaseWater 40.79 Ceteareth-20 6.84 Citric Acid 0.04 Potassium Citrate 0.17Propylene Glycol 21.05 Phenoxy Ethanol 1.05 Emulsion concentrate Total100.00

Examples 1 and 1A show a surfactant ratio of Ceteareth-20:sorbitanlaurate: cetyl alcohol of 6.5:1.5:2.0 wherein propylene glycol isintroduced in one stage to the aqueous phase of the composition. Thisproduct separates on standby, has poor in-can redispersability andrequires continuous mixing in process which is costly in large scalemanufacture.

Example 2

20% PG/pH 5 % w/w Part 1 Petrolatum 7.90 Mineral Oil 5.26 IsopropylMyristate 7.90 Cyclomethicone 5.26 Cetyl Alcohol 1.05 Sorbitan Laurate4.74 Part 2 Water 40.79 Ceteareth-20 4.74 Citric Acid 0.04 PotassiumCitrate 0.17 Part 3 Propylene Glycol 21.05 Phenoxy Ethanol 1.05Clobetasol Propionate 0.05 Emulsion concentrate Total 100.00

Example 2 shows a surfactant ratio of Ceteareth-20:sorbitanlaurate:cetyl alcohol of 4.5:4.5:1.0.

Example 3

17% PG/pH 5 % w/w Part 1 Petrolatum 5.26 Mineral Oil 5.26 IsopropylMyristate 10.53 Cyclomethicone 2.63 Cetyl Alcohol 1.05 Sorbitan Laurate4.74 Part 2 Water 46.58 Ceteareth-20 4.74 Citric Acid 0.08 PotassiumCitrate 0.13 Part 3 Propylene Glycol 17.90 Phenoxy Ethanol 1.05 Desonide0.05 Emulsion concentrate Total 100.00

Examples 3 shows a surfactant ratio of Ceteareth-20:sorbitanlaurate:cetyl alcohol of 4.5:4.5:1.0.

Example 4

5% PG % w/w Part 1 Petrolatum 5.00 Mineral Oil 5.00 Isopropyl Myristate5.00 Cyclomethicone 5.00 Cetyl Alcohol 1.00 Sorbitan Laurate 4.00 Part 2Water 58.686 Ceteareth-20 5.00 Citric Acid 0.20 Potassium Citrate Part 3Propylene Glycol 5.00 Phenoxy Ethanol 1.00 Betamethasone-17-Valerate0.114 Part 4 Hydrocarbon Propellant P70 5.00 Total 100.00

Example 4A

5% PG % w/w Part 1 Petrolatum 5.26 Mineral Oil 5.26 Isopropyl Myristate5.26 Cyclomethicone 5.26 Cetyl Alcohol 1.05 Sorbitan Laurate 4.21 Part 2Water 61.80 Ceteareth-20 5.26 Citric Acid 0.21 Potassium Citrate Part 3Propylene Glycol 5.26 Phenoxy Ethanol 1.05 Betamethasone-17-Valerate0.12 Emulsion concentrate Total 100.00

Examples 4 and 4A show a surfactant ratio of Ceteareth-20:sorbitanlaurate:cetyl alcohol of 5.0:4.0:1.0.

Example 5

10% PG % w/w Part 1 Petrolatum 5.00 Mineral Oil 5.00 Isopropyl Myristate5.00 Cyclomethicone 5.00 Cetyl Alcohol 1.00 Sorbitan Laurate 4.00 Part 2Water 53.686 Ceteareth-20 5.00 Citric Acid 0.20 Potassium Citrate Part 3Propylene Glycol 10.00 Phenoxy Ethanol 1.00 Betamethasone-17-Valerate0.114 Part 4 Hydrocarbon Propellant P70 5.00 Total 100.00

Example 5A

10% PG % w/w Part 1 Petrolatum 5.26 Mineral Oil 5.26 Isopropyl Myristate5.26 Cyclomethicone 5.26 Cetyl Alcohol 1.05 Sorbitan Laurate 4.21 Part 2Water 56.53 Ceteareth-20 5.26 Citric Acid 0.21 Potassium Citrate Part 3Propylene Glycol 10.53 Phenoxy Ethanol 1.05 Betamethasone-17-Valerate0.12 Emulsion Concentrate Total 100.00

Examples 5 and 5A show a surfactant ratio of Ceteareth-20:sorbitanlaurate:cetyl alcohol of 5.0:4.0:1.0.

The examples 2-5A show good physical stability, utilise less expensivemanufacturing techniques and show good redispersability.

Example 6

FIG. 1 shows the preparation of an ethanol-free 0.05% clobetasolpropionate foam of the same type as example 2 according to one preferredprocess according to the invention. This process has been successfullyscaled up as follows.

Petrolatum, light mineral oil, isopropyl myristate, sorbitan monolaurateand cetyl alcohol are added in specified quantities to the primarycompounding tank as the oil phase. This phase is mixed in the tank andheated to 75-80° C. Cyclomethicone is added and mixing is continued at75-80° C. until the oil phase is uniform in consistency.

To make the water phase, purified water, citric acid and potassiumcitrate are added into a kettle. This water phase mixture is mixed andheated to 80-85° C. Ceteareth-20 is then added and mixing is continuedat 80-85° C. until complete dissolution of all components occurs.

The third part containing the active agent (“the active phase”) isprepared by adding specified quantities of propylene glycol andphenoxyethanol into a kettle. Mixing of this part is commenced, theactive agent, clobetasol propionate is added and the phase is heated to55-60° C. Mixing is continued until complete dissolution of allcomponents occurs. The temperature of this part is allowed to cool, oris cooled in a water bath to 30° C.

Approximately 70% of the water phase mixture is then added to the oilphase mixture in the primary compounding tank. The two phases are mixedtogether and heated to 85-90° C. The approximately 30% remaining of thewater phase is cooled to 20-25° C. in a chilled water bath. Aftercontinued mixing of the oil/water phase in the primary compounding tankand cooling of the mixture to 72-78° C., the remainder of the waterphase mixture (approximately 30%) is added to the oil/water phase in theprimary compounding tank. Simultaneously, cooling is commenced toachieve a temperature of 35-40° C.

The content of the active phase kettle is added to the oil/water phasemixture in the primary compounding tank. Mixing is continued and thetemperature is lowered to 20-25° C.

The resultant composition is dispensed into cans at ambient temperature.

Example 7

This example details the preparation of a Desonide formulation accordingto one preferred process of the invention. The method results in a 17%Propylene Glycol and Desonide composition. This process has not beenscaled up.

The item numbers in the following composition listing correspond to theitem numbers in the process description which follows.

% w/w without Item No. Ingredient % w/w Propellant Part 1 1 Snow WhitePetrolatum 5.00 5.263 2 Lt Mineral Oil (Drakeol 5) 5.00 5.263 3Isopropyl Myristate 10.00 10.526 4 ST-Cyclomethicone 5-NF 2.50 2.632 5Cetyl Alcohol 1.00 1.053 6 Sorbitan Laurate (Crill 1) 4.50 4.737 Part 2(Part 2A = 70%, Part 2B = 30%) 7 Purified water 44.2525 46.582 8Ceteareth-20 4.50 4.737 9 Citric Acid, anhydrous 0.076 0.080 10Potassium Citrate, monohydrate 0.124 0.131 Part 3 11 Propylene Glycol17.00 17.895 12 Phenoxyethanol 1.00 1.053 13 Desonide 0.0475 0.050 Part4 14 Propellant P70 5 TOTAL 100.00 100.00

Items 1 to 6 are added to the mixing vessel, stirred and heated to60-80° C. to form the oil phase. The temperature is maintained orre-established before adding the water phase (see below).

To prepare the water phase, water at room temperature, anhydrous citricacid and potassium citrate, monohydrate are added to a suitably sizedvessel and stirred together. Ceteareth-20 is added, and the mixture isheated to a maximum of 50° C. until the ceteareth-20 is completelydissolved.

The water phase is separated into two parts. About 30% of the waterphase mixture is cooled to 20-30° C. The remaining 70% of the waterphase mixture is added to the oil phase mixing vessel at its existenttemperature. The mixing vessel containing the oil phase and most of thewater phase is heated to 80-85° C. with thorough mixing to ensureuniformity. The temperature should be held at this level for about 10minutes to assist in obtaining uniformity. The mixture will be a waterin oil emulsion and will be very white in colour. The conductivity willbe less than 100 μs/cm.

The oil in water mixture should be allowed to cool to about 73° C. Whenapproaching the assembly temperature the rate of cooling should be nomore than 1° per minute. At the assembly temperature the Δconductivitychanges from a large negative value to an almost constant value.

When the mixing vessel reaches about 73° C. as described, the remaining30% of the water phase which is at 20-30° C. is added and the mixingvessel is immediately cooled. Rapid addition of the remaining quantityof water phase is desirable, and the temperature of the mixture shouldbe approximately 60° C. at the completion of the addition of theremaining water phase mixture.

Phase 3 containing propylene glycol is prepared by adding items 11 to 13to a suitable vessel and heating until the Desonide is dissolved. Afterdissolution of the Desonide, the mixture should be cooled to less than30° C. The oil in water emulsion mixture should be cooled to about35-40° C. by stirring and phase 3 is then added at a rate so that theentire mixture is not added until at least 5-10 minutes has elapsed. Anunsatisfactory addition rate will be evidenced by the presence of abilayered product having an oily film on top upon standing.

The mixing vessel containing all components is cooled by stirring toabout 25-30° C. The resultant emulsion should be maintained at about20-25° C. before filling and should remain homogenous for at least 48hours without stirring.

Temperatures may vary up to about 5° C. depending on the sorbitanlaurate (oil phase) used. Conductivity tests are recommended todetermine the set point or assembly temperature of the microemulsion.

Example 8

This example demonstrates the effect on the compositions of varying theparameters of surfactant ratio, pre set point temperature variation andpost set point cooling rate.

Table 1 summarises the effects of varying the parameters of thepreparation of mainly 1.5 kg batches of compositions according topreferred aspects of the invention. As is shown in the table, the ratioof Ceteareth-20:sorbitan laurate is adjusted, the temperature of thephase 1 and phase 2 mixes prior to combination, and subsequent tocombination, is adjusted and the cooling rate of the combination of thetwo phases is adjusted and observations of the appearance, stability andparticle size are made. Batch numbers 367-14, 367-16, 367-22, E207/1/1and 328-68 were considered successful. FIG. 2 is a graphicalrepresentation of the method of this example charting the rate ofaddition of the various components of the compositions.

TABLE 1 Summary of Scale-up Process Development E foams in 1.5 kgBatches: Desonide P1 = 442 g  P2 = 773 g  P3 = 285 g Clobetasolpropionate P1 = 482 g  P2 = 686 g  P3 = 332 g Ceteareth- 20 to StabilityBatch Sorbitan Cooling Rate Observations during P2 Size Emulsion at Nolaurate Temp P1-P2 P2 addition to 40° C. addition (Microscope)appearance R.T. Desonide E 367-12 5.0:4.0 82° C.-82° C. 100 ml pipetteQuickly to Went translucent then white Many White, leaves <12 hrMaintained 40° C. with tap before P2 completely added 1-2 μm whiteresidue on water, 5-10 min glass 367-14 4.5:4.5 82° C.-82° C. 50 mlpipette Quickly to Went translucent later than ≦1 μm White but less >5days Maintained 40° C. with tap for 367-12, stayed longer residue onglass water, 5-10 min before going white before P2 than 367-12completely added 367-16 4.5:4.5 75° C.-75° C. Pump - 130 35 min to coolSame as 367-14 <1 μm White, but quite >5 days (65° C.) ml min⁻¹ to 40°C. clear on glass 367-18 4.0:5.0 75° C.-75° C. Pump - 130 35 min to coolWent translucent later than ≦1 μm <1 day, (65° C.) ml min⁻¹ to 40° C.for 367-14, went white just just see after P2 added 367-22 4.5:4.5 72°C.-80° C. Pump - 112 Cooling Went translucent at 6 min, <<1 μmBlue-White >5 days (68° C.) ml min⁻¹ begun then remained quite V cleanon glass, for 6 m 6 s immediately - translucent after P2 added. looksvery High speed for 25 min to transparent remainder, 40° C. <1 minClobetasol propionate E207/ 4.5:4.5 75° C.-75° C. Hand poured Air cooledin Stayed quite translucent. <<1 μm Blue-White >5 days 1/1 not about 45min V clean on glass, 500 ml maintained looks very transparent 328-684.5:4.5 72° C.-80° C. Pump - 112 ml Cooling Went translucent at 5 min,<<1 μm just Blue-White >5 days (68° C.) min⁻¹ for 5 min begun thenremained quite see dots V clean on glass, High speed for immediately -translucent after P2 added. looks transparent remainder (2 min) 25 minto 40° C. KEY: P1—Phase 2 (oil) P2—Phase 2 (aqueous) P2 addition: 100 mlpipette - Constant, stop start using a 100 ml pipette Pump - constantaddition using a peristaltic pump. P2 would cool in the tubing givingresulting in the temperature shown in brackets.

Example 9

FIG. 3 shows the timeline of a preferred process of preparation of alarge scale 15 kg Desonide composition according to one aspect of theinvention. The timeline shows a slow addition of the water phase untilinversion of the phases occurs, determined by conductance measurements,whereupon rapid addition of the remainder of the water phase iseffected.

The resultant composition is a blue white emulsion which leaves noresidue on glass. Only a small amount of foaming occurs mostly duringthe rapid addition of the remainder of the water phase. Temperature ofthe mix was maintained at 70-75° C. during mixing but cooling wasinitiated immediately the addition of the water phase had beencompleted. The majority of particles reviewed under a microscope weremuch less than 1 μm in diameter. The composition remained stable at 3days.

FIG. 4 is a graphical representation of the process of this examplechanging the rate of addition of the various components of thecomposition.

Example 10

This example demonstrates the effect of varying the ratio of emulsifiersin one composition prepared according to an embodiment of the inventionwherein the pharmaceutically active ingredient is betamethasone valerateand the emulsifiers are Ceteareth-20, sorbitan laurate and cetylalcohol. It also shows the effect of varying the manner of addition ofthe water phase; either all at once, or in two separate stages, thefirst stage being added at a slower rate than the second stage. FIG. 5shows the results of this example graphically. The acronym “BMV” isBetamethasone valerate.

The compositions E208/2/1-E2081218 are prepared as follows in accordancewith differing preferred embodiments of the invention:

-   -   E208/2/1-4.0:5.0:1.0 ratio of Ceteareth-20:sorbitan        laurate:cetyl alcohol, all water phase added in one hit—heated        to 81° C.    -   E208/2/2-4.5:4.5:1.0 ratio of Ceteareth-20:sorbitan        laurate:cetyl alcohol, all water phase added in one hit—heated        to 82° C.    -   E208/2/3-5.5:3.5:1.0 ratio of Ceteareth-20:sorbitan        laurate:cetyl alcohol, all water phase added in one hit—heated        to 94° C.    -   E208/2/4-5.0:4.0:1.0 ratio of Ceteareth-20:sorbitan        laurate:cetyl alcohol, all water phase added in one hit—heated        to 84° C.    -   E208/2/5-4.5:4.5:1.0 ratio of Ceteareth-20:sorbitan        laurate:cetyl alcohol, all water phase added in one hit—heated        to 92° C.    -   E208/2/6-4.5:4.5:1.0 ratio of Ceteareth-20:sorbitan        laurate:cetyl alcohol, all water phase added in one hit—heated        to 78° C.    -   E208/2/7-5.0:4.0:1.0 ratio of Ceteareth-20:sorbitan        laurate:cetyl alcohol, water phase added in two portions (70/30        hot:cold) propylene glycol stirred when added—heated to 74° C.    -   E208/2/8-5.0:4.0:1.0 ratio, of Ceteareth-20:sorbitan        laurate:cetyl alcohol water phase added in two portions (70/30        hot:cold) propylene glycol not stirred when added—heated to 74°        C.

This example shows that a microemulsion meeting the objects of theinvention can be made at varying surfactant ratios.

In order to determine the point at which a microemulsion is formed,conductance tests are recommended. The conductivity will dropdramatically immediately phase assembly occurs at the set point of themicroemulsion. Utilising the compositions E208/2/7, E208/2/8, E208/2/6and E208/2/4 (left to right across the key), FIG. 6 graphs conductivityof the compositions against the temperature of the water/oil phase mixand shows the conductivity response from heating to the assemblytemperature and subsequent cooling and addition of active phase. Theuppermost section, or assembly temperature range, of the conductivityplot demonstrates the trend that the set point of compositions accordingto the invention can be reduced by decreasing the relative proportion ofhydrophilic surfactant in the surfactant system. The assemblytemperature is also lowered when the water phase is split into twoaliquots. It is postulated that splitting the water phase has the sameeffect as reducing the relative proportion of hydrophilic surfactant andsubsequently lowering the assembly temperature for the microemulsion.

Example 11

This example demonstrates the effect on the appearance and particle sizeof varying the parameters of the processes hereinbefore described. Table2 shows that the phase in which the surfactant is added, and thepresence or absence of non-surfactant, amphiphilic substances in thecomposition prior to emulsification of the compositions, has an effecton the particle size of the composition. In the context of the example,it will be appreciated that the compositions meeting the objects of theinvention are those wherein the water phase is added to the oil phase,Ceteareth-20 is present in the water phase, and the remainingsurfactants are present in the oil phase, and wherein the addition ofthe non-surfactant amphiphilic components of the composition are addedafter emulsification of the composition at the phase assemblytemperature. In this case, the composition appears to have acceptablestability, and a particle size of less than 0.2 μm.

TABLE 2 Surfactant addition Sorbitan Polyol & Phenoxy Particle sizeProcess description Ceteareth-20 laurate Cetyl alcohol ethanol additionAppearance (μm) Comments Water phase added to oil Oil phase Oil phaseOil phase Water phase (before White liquid <20 Creaming observed withinphase emulsification) 24 hours Water phase added to oil Split betweenOil phase Oil phase Water phase (before White liquid <20 Creamingobserved within phase oil phase and emulsification) 24 hours water phaseWater phase added to oil Water phase Oil phase Oil phase Water phase(before White liquid <20 Creaming observed within phase emulsification)24 hours Water phase added to oil Water phase Oil phase Oil phaseEmulsion (after Bluish-white, <0.2 No creaming observed phaseemulsification) translucent over several days liquid Oil phase added towater Oil phase Oil phase Oil phase Water phase (before White liquid <20Creaming observed within phase emulsification) 24 hours Oil phase addedto water Water phase Oil phase Oil phase Water phase (before Whiteliquid <20 Creaming observed within phase emulsification) 24 hours

Example 12

In order to demonstrate the chemical and physical stability ofcompositions prepared according to the process of the invention comparedto those of the prior art, the following tests were carried out. In thecompositions prepared according to the process of the invention (12B)the polyol and/or alcohol are added in a third phase afteremulsification and cooling of the oil in water emulsion formed in thefirst stage of the process. In the compositions prepared according toprior art processes (12A) the polyol and/or alcohol are added to the oilor water phase prior to emulsification and cooling of the composition.Table 3 shows the 6 month stability data associated with a compositionaccording to Example 12A; a prior art type composition.

Example 12A (Prior art)

% w/w without Item No. Ingredient % w/w Propellant Part 1 1 ClobetasolPropionate 0.0475 0.050 2 Snow White Petrolatum 7.50 7.895 3 Lt MineralOil (Drakeol 5) 5.00 5.263 4 Isopropyl Myristate 7.50 7.895 5ST-Cyclomethicone 5-NF 5.00 5.263 6 Cetomacrogol 1000 BP 6.50 6.842 7Cetyl Alcohol 2.00 2.105 8 Sorbitan Laurate (Crill 1) 1.50 1.579 Part 29 Purified water 38.7525 37.803 10 Citric Acid, anhydrous 0.04 0.042 11Potassium Citrate, monohydrate 0.16 0.168 12 Propylene Glycol 20.0021.053 13 Phenoxyethanol 1.00 1.053 Part 3 14 Propellant P70 5 TOTAL100.00 100.00

Preparation:

-   -   1. Part 1 preparation: Add Items 2 to 8 into the mixing vessel.        Heat to 60° C. and stir to combine. Maintain temperature before        adding Clobetasol Propionate. Stir until dissolved then increase        the temperature to 80-85° C. in preparation for part 2 addition.    -   2. Part 2 preparation: Add items 9 to 13 to a mixing vessel and        heat to 80-85° C.* with stirring until a clear solution is        formed.    -   3. Emulsification: Stir part 1 well (without introducing air)        then add part 2. Initially add part 2 at a slower rate. During        part 2 addition, a period of higher viscosity will occur that        may require an increased stirring speed, for a short time, to        ensure thorough mixing.    -   4. Homogenisation: Stir and cool the emulsion to 40° C. (cool at        a reasonably fast rate). Homogenise the emulsion if the average        particle size is >2.5 μm or the maximum particle size is >15 μm.        Stir cool the emulsion to 25° C.

TABLE 3 Spay Storage Pressure Foam Re-disp. Re-disp. Rate temperatureTest time Clobetasol % of Phenoxy- % of Weight psig @ pH @ at at Foam atFoam at Foam at gs⁻¹ ° C. point % T = 0 ethanol % T = 0 loss (g) 25° C.25° C. 10° C. 15° C. 15° C. 25° C. 35° C. 21° C. Initial 0.0502 — 1.060— — 44 6.04 — — 0.5 1.0 — 4.2  5° C.  1 month 0.0499 99.4 1.051 99.2  2months 0.0500 99.6 1.050 99.1  3 months 0.0501 99.8 1.053 99.3  6 months0.0502 100.0 1.046 98.7  9 months 12 months 25° C.  3 months 0.0502100.0 1.047 98.7 0.023 ± 43 6.07 5 4 0.5 1.0 1.5 4.2 0.009  6 months0.0495 98.6 1.043 98.4 0.043 ± 43 6.05 6 5 0.5 0.5 1.5 2.9 0.007  9months 12 months 30° C.  2 months 0.0498 99.1 1.045 98.5 0.024 ± 44 6.035 3 0.5 1.0 — 4.3 0.006  3 months 0.0499 99.3 1.045 98.6 0.030 ± 45 6.126 5 0.5 1.0 1.5 3.1 0.008  6 months 0.0496 98.8 1.040 98.1 0.076 ± 426.07 6 5 0.5 0.5 1.5 4.4 0.007  9 months 12 months 40° C.  1 month0.0497 98.9 1.046 98.6 0.039 ± 43 6.04 5 4 0.5 1.0 — 4.6 0.006  2 months0.0496 98.7 1.045 98.6 0.057 ± 43 6.03 6 5 0.5 1.0 — 4.1 0.005  3 months0.0496 98.8 1.043 98.3 0.083 ± 45 6.13 6 5 0.5 1.0 1.5 4.6 0.007  6months 0.0490 97.5 1.045 98.5 0.162 ± 42 6.06 6 6 0.5 0.5 1.5 4.2 0.011

Example 12B

% w/w without Item No. Ingredient % w/w Propellant Part 1 1 Snow WhitePetrolatum 7.50 7.895 2 Lt Mineral Oil (Drakeol 5) 5.00 5.263 3Isopropyl Myristate 7.50 7.895 4 ST-Cyclomethicone 5-NF 5.00 5.263 5Cetyl Alcohol 1.00 1.053 6 Sorbitan Laurate (Crill 1, USA) 4.50 4.737Part 2 (Part 2A = 70%, Part 2B = 30%) 7 Purified water 38.7525 40.792 8Cetomacrogol 1000 BP 4.50 4.737 9 Citric Acid, anhydrous 0.040 0.042 10Potassium Citrate, monohydrate 0.160 0.168 Part 3 11 Propylene Glycol20.00 21.053 12 Phenoxyethanol 1.00 1.053 13 Clobetasol Propionate0.0475 0.050 Part 4 14 Propellant P70 5 TOTAL 100.00 100.00

Preparation:

-   -   1. Part 1 preparation: Add Items 1 to 6 into the mixing vessel.        Heat to 60-80° C. and stir to combine. Maintain temperature        before adding Part 2A.    -   2. Part 2 preparation: Add Item 7 (Water) at room temp, Item 9        (Citric acid, anhydrous) and Item 10 (Potassium Citrate,        monohydrate) to a suitably sized vessel. Stir well and add all        of Item 8 (Cetomacrogol 1000 BP). Heat to a maximum of 50° C.        until the Cetomacrogol has completely dissolved (above 50° C.        the cetomacrogol melts and will clump to form a large mass).    -   3. Part 2 separation: Perform a weight check on part 2 then        split into        -   Part 2A—containing 70% of Part 2        -   Part 2B—containing 30% of Part 2    -   Cool part 2B to 20-30° C. (ideally 20-25° C.).    -   4. Part 2A addition: Add part 2A to the mixing vessel. Part 2A        may be added immediately after dissolving the Cetomacrogol when        hot, or if it was previously prepared and had cooled to room        temp.    -   5. Heat the mixing vessel to at least 80-85° C. (part 1+part        2A), with good mixing and hold for 10 min When measuring the        conductivity, this will be <100 μS/cm, if not, increase the        temperature.    -   Allow the mixing vessel to slowly cool to 73.0° C. When        approaching the target temperature (73.0° C.) the cooling rate        should be no more than 1° C. per min. This should correspond to        the maximum clarity of the emulsion. It is also the point where        ΔConductivity changes from a large negative value to almost        constant zero.    -   6. Addition of Part 2B: When the mixing vessel reaches 73.0° C.,        pump in part 2B (which is at 25° C.) and immediately begin        cooling the mixing vessel. Addition of part 2B should be        completed within 90 s. The temperature of the mixture should be        about 60° C. at the completion of part 2B addition.    -   7. Addition of Part 3: Stir and cool the mixing vessel to        35-40° C. Part 3 should be previously prepared by adding Items        11 to 13 into a suitable vessel and heating until the Clobetasol        is dissolved. Cool Part 3 to <30° C. after the Clobetasol has        dissolved and add to the mixing vessel at a rate to take at        least 5-10 min.    -   8. Stir cool the mixing vessel to 25-30° C. (25° C. preferable).        Perform a weight check. Base emulsion should be maintained at        20-25° C. before filling. Base emulsion should remain        homogeneous for at least 48 hr without stirring.

Table 4 shows 3 month stability data associated with a compositionaccording to Example 12B, a composition prepared in accordance with oneform of the invention.

TABLE 4 Storage Clobetasol % Weight Pressure Foam Re- Foam Foam Foamtempera- Test time Propionate of Phenoxy- % of loss psig @ pH @ disp. atat at Package ture ° C. point % T = 0 ethanol % T = 0 (g) 25° C. 25° C.at 5° C. 15° C. 25° C. 35° C. interaction Initial 0.0497 — 1.034 — — 316.20 — 3.0 1.5 2.0 — 25° C. 3 months 0.0491 98.8 1.0409 100.7 0.03 306.23 1 4.5 2.0 1.0 Lining - no change. Gasket, spring, valve cup - nochange, valve body and stem-Slightly yellowed. No signs of attack onscratch (clean and bright) 6 months 40° C. 1 month 0.0491 98.8 1.028899.5 0.01 28 6.21 1 1.5 1.0 1.5 Lining - no change. Gasket, spring,valve cup, valve body and stem-no change. No signs of attack on scratch(clean and bright) 3 months 0.0487 98.0 1.0262 99.2 0.06 30 6.20 1 4.01.5 2.5 Lining - no change. (10° C.) Gasket, spring, valve cup - nochange, valve body and stem-Slightly yellowed. No signs of attack onscratch (clean and bright) 6 months

Comparing Tables 3 and 4 it can be seen that the active ingredient,clobetasol propionate and the preservative, phenoxyethanol, which areboth routinely analysed, are not affected by the physical form of theemulsion (i.e. prior art versus a composition according to theinvention).

Example 13

The physical stability of the formulation prepared according to themethods of the invention has been confirmed using a TurbiscanTransmission Plot which shows that after 4 days, the dispersed phase ishomogenously distributed throughout the sample meaning that no phaseseparation has occurred.

Surfactant Ratio (Ceteareth-20:Sorbitan Laurate:Cetyl Alcohol)4.0:5.0:1.0 4.5:4.5:1.0 5.0:4.0:1.0 5.5:3.5:1.0 6.0:3.0:1.0 Part 1Petrolatum 5.00 5.00 5.00 5.00 5.00 Mineral Oil 5.00 5.00 5.00 5.00 5.00Isopropyl 5.00 5.00 5.00 5.00 5.00 Myristate Cyclo- 5.00 5.00 5.00 5.005.00 methicone Cetyl 1.00 1.00 1.00 1.00 1.00 Alcohol Sorbitan 5.00 4.504.00 3.50 3.00 Laurate Part 2 Water 58.80 58.80 58.80 58.80 58.80Ceteareth-20 4.00 4.50 5.00 5.50 6.00 Citric Acid 0.12 0.12 0.12 0.120.12 Potassium 0.08 0.08 0.08 0.08 0.08 Citrate Part 3 Propylene 5.005.00 5.00 5.00 5.00 Glycol Phenoxy 1.00 1.00 1.00 1.00 1.00 Ethanol Part4 Hydrocarbon 5.00 5.00 5.00 5.00 5.00 Propellant P70 Total 100.00100.00 100.00 100.00 100.00 Turbiscan Creaming Creaming Slight StableStable @ >4 days Creaming

Example 14

Using the formulation set out below and made using the procedureillustrated in FIG. 7, a phase II clinical trial was conducted asdescribed.

17% PG/pH 5 % w/w Part 1 White Petrolatum 5.26 Light Mineral Oil 5.26Isopropyl Myristate 10.53 Cyclomethicone 2.63 Cetyl Alcohol 1.05Sorbitan Monolaurate 4.74 Part 2 Purified Water 46.58 Polyoxyl 20Cetostearyl Ether 4.74 Citric Acid Anhydrous 0.08 Potassium Citrate 0.13Part 3 Propylene Glycol 17.90 Phenoxy Ethanol 1.05 Desonide (micronized)0.05 Emulsion concentrate Total 100.00

The randomized phase II clinical trial involved 106 patientsdemonstrating mild to moderate atopic dermatitis who underwent a 4 weektreatment and were followed up three weeks subsequently. Patients aged 3months to 17 years were administered the above composition formulated asa foam in a ratio of 2:1 (desonide composition: vehicle absentdesonide). The primary endpoints of the study were determined to be asfollows:

Investigator's Static Global Assessment; clear (0) or almost clear (1),and

Erythema; 0 or 1, and

Induration/Papulation; 0 or 1, and

ISGA; minimum improvement of 2 grades.

There were multiple secondary endpoints.

The Part 2 results showed that where the primary endpoint was validated,there was a 53% response rate in patients treated with the desonideformulation and a 12% response rate in patients treated with the vehiclelacking the active agent desonide (placebo). The response rate to theplacebo was as expected. The response rate to the desonide formulationwas nearly double the expected rate (53% versus 27%). The formulationsaccording to the invention show surprising and unexpected advantagesover the expected response.

Example 15

A 0.12% betamethasone valerate sub-micron emulsion formulation wasprepared to demonstrate the ability to dissolve a pharmaceuticallyactive ingredient in the oil phase. The following formulation wasprepared.

Item No. Ingredient Trade Name 1 Octyl dimethyl PABA Escalol 507 10.00 2Betamethasone Valerate BMV 0.12 3 Mineral Oil Drakeol 9 10.00 4 SorbitanLaurate Crill 1 4.00 5 Ceteareth-20 Cetomacrogol 1000BP 5.00 6 CetylAlcohol Cetyl Alcohol 1.00 7 Purified Water Water 64.18 8 Citric AcidCitric Acid Anhydrous 0.11 9 Potassium Citrate Potassium Citrate 0.09 10Phenoxyethanol Phenoxyethanol 0.50 11 P70 Propellent 70 5.00* Total:100.00

The formulation was prepared according to the following protocol:

-   -   Combine items 1 and 2. Stir until completely dissolved.    -   Add items 3, 4, 5 and 6. Heat to 60° C. and stir until        dissolved.    -   In a separate beaker, combine items 7, 8, 9 and 10. Stir until        dissolved.    -   With stirring add 70% of the water phase to the warm, clear oil        phase. Continue stirring and heating while recording the        temperature and the conductivity.    -   Continue heating and stirring to just past the assembly        temperature (approx. 74° C.). Remove the emulsion from heat and        place on a cool stirrer.    -   Continue stirring and add the remaining water phase at the        temperature when conductivity is at a maximum (approx. 70-72°        C.).    -   Stir cool to 30° C. Top up with water to account for evaporative        loss.    -   Test pH and adjust to pH 4 (if required)

The physical characteristics the formulation is summarised as follows:

Formulation SME Appearance Translucent, water thin emulsion pH (@RT)3.97 DLS mean diameter (nm) 64.0 SPOS (% volume > 0.5 um) 0.109

Example 16

Item No. Formulation No F743/1/4 F743/1/6 Part 1 - Oil phase 1 WhitePetrolatum, USP 5.0 5.0 2 Light Mineral Oil, NF 5.0 5.0 3 IsopropylMyristate, NF 5.0 5.0 4 Olive Oil, NF 1.0 1.0 5 Butyrospermum Parkii(Shea Butter) 2.0 2.0 6 Sorbic Acid, NF 0.05 0.05 7 Cetyl Alcohol, NF0.75 0.75 8 Sorbitan Monolaurate, NF 5.63 5.63 Part 2 - Water phase 9Water 36.09 36.09 10 Potassium Sorbate, NF 0.05 0.05 11 Polyoxyl 20cetostearyl ether, NF 5.63 5.63 Part 3 - Humectant phase 12 Water 23.43.8 13 Glycerin, USP 10.0 10.0 Part 4 - Lactate phase 14 Water 0.13 6.6715 Sodium Hydroxide pure, NF 0.044 2.22 16 Lactic Acid (90% solution),NF 0.22 11.11 TOTAL 100.00 100.00

Example 16 shows a surfactant ratio of Polyoxy 20 cetostearylether:sorbitan monolaurate:cetyl alcohol of 7.5:7.5:1.0.

Preparation:

-   -   1. Part 1 preparation: Add Items 1 to 8 into the main mixing        vessel. Heat to 50-70° C. and stir to combine. The temperature        may be maintained or allowed to cool (e.g. if prepared on a        previous day) prior to adding Part 2A, depending on convenience.    -   2. Part 2 preparation: Add Item 9 (water) and Item 10 (potassium        sorbate) to a suitably sized vessel at room temperature and mix        until dissolved. Add Item 11 (Cetomacrogol 1000 BP) with        stirring and continue to stir until completely dissolved. This        phase may be heated up to a maximum of 50° C. to assist        Cetomacrogol dissolution (above 50° C. the cetomacrogol melts        and may clump together, forming a large mass).    -   3. Perform a weight check on Part 2 then divide into two        portions:        -   Part 2A—containing 80% of Part 2, and        -   Part 2B—containing 20% of Part 2.        -   Cool Part 2B to 20-30° C. (ideally 20-25° C.).    -   4. Part 2A addition: Add Part 2A to the mixing vessel (high        addition rate is OK). The temperature of Part 2A before addition        is not critical. Part 2A may be added immediately after        dissolving the Cetomacrogol when hot, or if it was previously        prepared and had cooled to room temp.    -   5. Heat the mixing main vessel containing Part 1 and 2A to at        least 80-85° C. with good mixing without aeration and hold for        10 min (just to ensure uniformity).    -   6. Allow the mixing vessel to slowly cool to the phase assembly        temperature (PAT) of 71.0-74.0° C. When approaching the PAT the        cooling rate should be no more than 1° C. per min. The PAT        should correspond to the maximum clarity of the emulsion.    -   7. Addition of Part 2B: When the mixing vessel reaches        71.0-74.0° C., pump in Part 2B (which is at 25° C.) and        immediately begin cooling the mixing vessel. Addition of Part 2B        must be completed within 60 s (faster pumping rates may be        used). Therefore, larger batches require faster pump speeds. The        temperature of the mixture should decrease to about 60° C. at        the completion of Part 2B addition (i.e. at least 10° C.        decrease within 1 min). To ensure adequate cooling for large        batches, Part 2B may be cooled to <20° C. If the mixing vessel        cools to <71.0° C. before Part 2B can be added, the mixing        vessel may be reheated to 74.0° C. before the addition of Part        2B. During this second heating it is not necessary to reach        80° C. This example suggests that it is better to be at the        upper end of the 71-74° C. range for the Part 2B addition.    -   8. Addition of Part 3: Part 3 should be previously prepared by        adding Items 12 (water) and 13 (glycerin) into a suitable vessel        and mixing. Stir and cool the main mixing vessel to <30° C. and        ensure thorough mixing without aeration. Add Part 3 to the main        mixing vessel at a slow rate that takes at least 5 min to        complete. (Note: if the Part 3 addition is too fast, or the        mixing too slow during Part 3 addition, larger oil-drops can        form, which can subsequently separate to the top of the emulsion        on standing)    -   9. Addition of Part 4: Part 4 should be previously prepared by        first dissolving Item 15 (sodium hydroxide) into Item 14 (water)        in a suitable vessel, whilst mixing. This solution is cooled to        room temperature. Item 16 (lactic acid) is added to a separate        vessel and stirred gently. Whilst stirring Item 16, the caustic        solution (comprising Items 14 and 15) is slowly added, mixed        until uniform and cooled to room temperature. Add Part 4 to the        main mixing vessel (with thorough mixing) at a slow rate that        takes at least 5 min to complete (Note: if the Part 4 addition        is too fast, or the mixing too slow during Part 4 addition,        larger oil-drops can form, which can subsequently separate to        the top of the emulsion on standing).    -   10. Stir cool the mixing vessel to 25-30° C. (25° C.        preferable). Perform a weight check. The base emulsion should be        maintained at 20-25° C. before filling. The base emulsion should        remain homogeneous for at least 48 hr without stirring.

Example 17

Part 1 - Oil 1 White Petrolatum, USP 5.0 2 Light Mineral Oil 5.0 3Isopropyl Myristate, NF 5.0 4 Olive Oil, NF 1.0 5 Butyrospermum Parkii(Shea Butter) 2.0 6 Sorbic Acid, NF 0.05 7 Cetyl Alcohol, NF 0.75 8Sorbitan Monolaurate, NF 5.63 Part 2 - Water 9 Water 35.09 10 PotassiumSorbate, NF 0.05 11 Polyoxyl 20 cetostearyl ether, NF 5.63 Part 3 -Humectant phase 12 Water 6.64 13 Glycerin, USP 10.0 Part 4 - Lactatephase 14 Ammonium lactate (70%) solution 17.16 TOTAL 100.00

Example 17 shows a surfactant ratio of Polyoxy 20 cetostearylether:sorbitan monolaurate:cetyl alcohol of 7.5:7.5:1.0.

Preparation:

The formulation of Example 17 is prepared according to the preparationmethod described in Example 16 except that Part 4, the Lactate phase,comprises a 70% ammonium lactate solution.

Example 18

% w/w % w/w (without (with Ingredient Preservative) Preservative) Part 1(Oil Phase) Petrolatum 5.00 5.00 Isopropyl myristate 5.00 5.00 Mineraloil 5.00 5.00 Cyclomethicone 5.00 5.00 Cetyl alcohol 0.80 0.80 Sorbitanmonolaurate 4.00 4.00 Total Part 1 24.80 24.80 Part 2 (Water Phase)Purified water 58.96 57.46 Trisodium citrate dihydrate 0.20 0.20Anhydrous citric acid 0.04 0.04 Polyoxyl 20 cetostearyl ether 5.00 5.00Total Part 2 64.20 62.70 Part 3 (API Phase) Purified Water 10.00 10.00Pramoxine HCl 1.00 1.00 Total Part 3 11.00 11.00 Part 4 (PreservativePhase) Benzyl alcohol 0.00 1.50 Total Part 4 0.00 1.50 Hydrocarbonpropellant AP70 Total (Parts 1 to 4) 100.000 100.000 Aerosol Base FillWeight (g) 46.25 46.25 Propellant Fill Weight (g) 3.75 3.75 Total FillWeight (g) 50.00 50.00

Example 18 shows a surfactant ratio of Polyoxy 20 cetostearylether:sorbitan monolaurate:cetyl alcohol of 6.25:5.0:1.0.

Preparation:

-   -   1. Part 1 Preparation: Petrolatum, Isopropyl myristate, Mineral        oil, Cyclomethicone, Cetyl alcohol and Sorbitan Monolaurate are        added to a suitable stainless steel container at ambient        temperature and mixed, with gentle heating, until a single-phase        solution is formed.    -   2. Part 2 Preparation: Purified water, Anhydrous citric acid,        Trisodium citrate dihydrate and Polyoxyl 20 cetostearyl ether        are added to a suitable stainless steel container at ambient        temperature and mixed until a clear, colorless solution is        formed.    -   3. Part 3 Preparation: Pramoxine HCl and Purified water are        added to a suitable stainless steel container at ambient        temperature and mixed until a clear, colorless solution is        obtained.    -   4. Part 4 Preparation: Benzyl Alcohol only.    -   5. Heat Part 1—Oil Phase to 60° C. whilst stirring.    -   6. Heat Part 2—Water phase to 60° C. whilst stirring.    -   7. In a separate vessel, with cooling and heating capabilities,        transfer all of the Oil Phase and 2/3 of the Water Phase.    -   8. Heat the mixture whilst stirring and monitor temperature and        conductivity. Continue until the conductivity reaches the        plateau (around 1200 micro Siemens) at ˜65 C.    -   9. With additional heating, the conductivity will start to        decrease slowly. At this point (i.e. the phase assembly        temperature where the Sub-micron Emulsion (SME) is formed) add        the remaining 1/3 of the water phase (at a temperature between        room temperature and 60° C.).    -   10. Start cooling the SME mixture immediately. The conductivity        will decrease with the addition of the water phase (to ˜1400        micro Siemens) and will remain constant until the mixture is        cooled down to ambient temperature.    -   11. The API Phase is added to the SME mixture at ambient        temperature and mixed thoroughly. Conductivity will increase to        ˜2350 micro Siemens.    -   12. Perform an in-process test to confirm the pH of the Aerosol        Base.    -   13. Check Aerosol Base visually for homogeneity and        translucence.

Aerosol Filling and Crimping:

The aerosol base is filled into 35×125 mm PAM 8460 lined aluminumaerosol cans. When filling the composition with preservative system, theaerosol base and the benzyl alcohol are added in two separate portions.The inverted-use valves are inserted and the package is vacuum crimpedand subsequently gassed with hydrocarbon propellant AP70. Cans are leaktested, by immersion in a 55-58° C. water bath, then cooled to ambienttemperature and shaken briefly to mix the aerosol container's contents.

Example 19

This example demonstrates the stability of the 1% pramoxine HCl foamformulations of Example 18.

Foam Quality:

The foam has been developed primarily for use at room temperature (i.e.approx. 20° C.) and thus the foam quality is best at this temperature.As the foam is also likely to be dispensed at other temperatures, thefoam quality was evaluated following storage at 40° C., using SOP 75(SRA SOP NO. 75.04—Appearance of Emollient Foam (Revision 10 Dec. 2007),at two typical extremes in temperature (i.e. 10° and 30° C.).

The results are presented in the tables of FIGS. 10 and 11. Inconclusion, the unpreserved foam (Formula 692-15-21 in FIG. 10)collapses in size (after 6 months storage, test at 30° C.) onlyapproximately 30% after 1 minute, and passes the SOP 75 acceptancecriteria score of <3 at 1 minute. The benzyl alcohol preserved foam(Formula 692-15-24 in FIG. 11) collapses in size (after 6 monthsstorage, test at 30° C.) only approximately 30% after 1 minute, andpasses the SOP 75 acceptance criteria score of <3 at 1 minute.

Concentration of Pramoxine HCl:

The two formulations of Example 18 show the storage stability at 40° C.as represented in Table 5.

TABLE 5 Pramoxine HCl (%) assay Time Points Temperature 0 (° C.) Month 1Month 3 Month 6 Month w/w % 5 0.979 0.992 0.986 0.983 (without 25 0.9810.982 Preservative) 40 0.989 0.977 0.977 % w/w 5 0.969 0.972 0.972 0.976(with 40 0.967 0.956 0.962 preservative)

The unpreserved formulation exhibited 0.2% loss (compared to initialassay) after 6 months' storage at 40° C., hence is expected to meet ashelf life/expiry date of at least 24 months. The preserved formulationexhibited 0.7% loss (compared to initial assay) after 6 months' storageat 40° C., hence is expected to meet a shelf life/expiry date of atleast 24 months.

pH Stability:

The pH drift with time in the two formulations of Example 18 was testedand the results are represented in Table 6.

TABLE 6 pH of foam Time Points Temperature 0 (° C.) Month 1 Month 3Month 6 Month w/w % 5 4.57 4.63 (without 25 4.51 4.55 4.59 Preservative)40 4.53 4.56 4.58 % w/w 5 4.65 4.70 (with 40 4.63 4.70 preservative)

A pH range of 4.75±0.25 has been identified as acceptable for 1%pramoxine HCl foam's physical, chemical and packaging stability. Table 6shows that as the test progressed there was no significant drift in thepH of the foam expelled from the can.

In conclusion it will be appreciated that the process of the inventionallows the formation of a stable oil-in-water microemulsion orsub-micron emulsion which allows for the inclusion of a hydrocarbonpropellant so that a foam may be dispensed when the resulting product isin use. Moreover, the resultant foam appears stable and effective. Itwill be appreciated that the scope of the invention described herein isnot limited to the specific embodiments described herein in the examplesbut extends to the general principles of the invention as set out in thesummary and detailed description of the invention hereinabove.

1-16. (canceled)
 17. An oil in water microemulsion or sub-micronemulsion composition for dermal delivery of at least onepharmaceutically active ingredient, the composition comprising: at leastone pharmaceutically active ingredient; an oil in water microemulsion orsub-micron emulsion comprising an oil phase dispersed throughout a waterphase, said oil phase comprising at least one selected from the groupconsisting of an animal oil, a mineral oil, a vegetable oil, a silane, asiloxane, an ester, a fatty acid, a fat, a halogen compound, and analkoxylated alcohol, and at least one lipophilic surfactant, said waterphase comprising at least one hydrophilic surfactant and water; and anon-surfactant amphiphilic compound that is added to the compositionafter formation of said microemulsion or sub-micron emulsion and ismiscible in said water phase, wherein said pharmaceutically activeingredient is in said water phase or is in both said oil phase and saidwater phase, and the weight ratio of said at least one hydrophilicsurfactant to said at least one lipophilic surfactant is approximately9.0:1.0 to 2.0:3.0.
 18. The composition according to claim 17, whereinsaid oil phase comprises at least one occlusive agent selected from thegroup consisting of mineral oil and petrolatum, and at least onelipophilic surfactant.
 19. The composition according to claim 18,wherein said oil phase comprises a mixture of petrolatum and mineraloil, and at least one lipophilic surfactant.
 20. The compositionaccording to claim 17, wherein said amphiphilic compound is a watermiscible organic solvent selected from the group consisting of a glycol,a polyol, and mixtures thereof.
 21. The composition according to claim17, wherein said surfactants have an aggregated HLB number between 8.0and 15.0.
 22. The composition according to claim 21, wherein saidsurfactants have an aggregated HLB number between 10 and
 12. 23. Thecomposition according to claim 22, wherein said surfactants have anaggregated HLB number between 9.7 and 11.8.
 24. The compositionaccording to claim 17, wherein said pharmaceutically active ingredientis one or more water insoluble compounds selected from the groupconsisting of corticosteroids, vitamin D analogues, and vitamin Aanalogues.
 25. The composition according to claim 24, wherein saidpharmaceutically active ingredient is a corticosteroid.
 26. Thecomposition according to claim 25, wherein said corticosteroid isselected from the group consisting of desonide, clobetasol propionate,and betamethasone valerate.
 27. A method of medical or cosmetictreatment of a dermal condition comprising: applying to the skin of apatient requiring such treatment an effective amount of oil in water(O/W) microemulsion or sub-micron emulsion composition comprising: atleast one pharmaceutically active ingredient; an oil in watermicroemulsion or sub-micron emulsion comprising an oil phase dispersedthroughout a water phase, said oil phase comprising at least oneselected from the group consisting of an animal oil, a mineral oil, avegetable oil, a silane, a siloxane, an ester, a fatty acid, a fat, ahalogen compound, and an alkoxylated alcohol, and at least onelipophilic surfactant, said water phase comprising at least onehydrophilic surfactant and water; and a non-surfactant amphiphiliccompound that is added to said composition after formation of saidmicroemulsion or sub-micron emulsion and is miscible in said waterphase, wherein said pharmaceutically active ingredient is in said waterphase or is in both said oil phase and said water phase, and the weightratio of said at least one hydrophilic surfactant to said at least onelipophilic surfactant is approximately 9.0:1.0 to 2.0:3.0.
 28. Themethod according to claim 27, wherein said patient is a human.